scholarly journals Suan-Zao-Ren Decoction Ameliorate Synaptic Plasticity Through the Inhibition of JAK2/STAT3 Signaling Pathway in APP/PS1 Transgenic Mice

2020 ◽  
Author(s):  
Qing-Hua Long ◽  
Yong-Gui Wu ◽  
Li-Ling He ◽  
Li Ding ◽  
Ai-Hua Tan ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Synaptic Plasticity ◽  
Transgenic Mice ◽  
Nissl Staining ◽  
Stat3 Pathway ◽  
Plaque Deposition ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Tnf Α ◽  
Neurological Illnesses

Abstract Background: Suan-Zao-Ren Decoction (SZRD) has been widely used to treat neurological illnesses, like dementia, insomnia, and depression. However, mechanisms underlying SZRD’s improvement in cognitive function remains unclear. In this study, we examined SZRD’s effect on APP/PS1 transgenic mice as well as mechanisms associated with SZRD’s action in alleviating neuroinflammation and improving the synaptic plasticity. Methods: The APP/PS1 mice were treated with different dosages of SZRD (12.96 and 25.92 g/kg/d, in L-SZRD and H-SZRD groups, respectively) for four weeks. Morris water maze was conducted to determine changes in behaviors of the mice after the treatment. Meanwhile, in the samples of the hippocampus, Nissl staining and Golgi-Cox staining were used to detect the synaptic plasticity, Western blot (WB) was employed to test expressions of Aβ1-42, APP, ADAM10, BACE1, PS1, IDE, IBA1, GFAP, PSD95 and SYN, as well as the expressions of JAK2, STAT3 and their phosphorylation patterns to detect involvement of JAK2/STAT3 pathway. Besides, we examined the serum contents of IL-1β, IL-6, and TNF-α using ELISA.Results: Compared to the APP/PS1 mice without any treatment, SZRD, especially the L-SZRD, significantly ameliorated cognitive impairment of the APP/PS1 mice with decreases in the loss of neurons and Aβ plaque deposition as well as improvement of synaptic plasticity in the hippocampus (all P<0.05). Also, SZRD, in particular, the L-SZRD markedly inhibited the serum IL-6, IL-1β, and TNF-α, while reducing the expression of p-JAK2-Tyr1007 and p-STAT3-Tyr705 in the hippocampus of the APP/PS1 mice (all P<0.05). Conclusion: The SZRD, especially the L-SZRD, may improve the cognitive impairment and ameliorate the neural degeneration in APP/PS1 transgenic mice through decreasing Aβ accumulation and inhibiting neuroinflammation via JAK2/STAT3 pathway.

scholarly journals Suan-Zao-Ren Decoction ameliorates synaptic plasticity through inhibition of the Aβ deposition and JAK2/STAT3 signaling pathway in AD model of APP/PS1 transgenic mice

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Qing-Hua Long ◽  
Yong-Gui Wu ◽  
Li-Ling He ◽  
Li Ding ◽  
Ai-Hua Tan ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Synaptic Plasticity ◽  
Transgenic Mice ◽  
Nissl Staining ◽  
Stat3 Pathway ◽  
Plaque Deposition ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Tnf Α ◽  
Neurological Illnesses

Abstract Background Suan-Zao-Ren Decoction (SZRD) has been widely used to treat neurological illnesses, including dementia, insomnia and depression. However, the mechanisms underlying SZRD’s improvement in cognitive function remain unclear. In this study, we examined SZRD’s effect on APP/PS1 transgenic mice and mechanisms associated with SZRD’s action in alleviating neuroinflammation and improving synaptic plasticity. Methods The APP/PS1 mice were treated with different dosages of SZRD (12.96 and 25.92 g/kg/day, in L-SZRD and H-SZRD groups, respectively) for 4 weeks. Morris water maze was conducted to determine changes in behaviors of the mice after the treatment. Meanwhile, in the samples of the hippocampus, Nissl staining and Golgi-Cox staining were used to detect synaptic plasticity. ELISA was applied to assess the expression levels of Aβ1−40 and Aβ1−42 in the hippocampus of mice. Western blot (WB) was employed to test the protein expression level of Aβ1−42, APP, ADAM10, BACE1, PS1, IDE, IBA1, GFAP, PSD95 and SYN, as well as the expressions of JAK2, STAT3 and their phosphorylation patterns to detect the involvement of JAK2/STAT3 pathway. Besides, we examined the serum and hippocampal contents of IL-1β, IL-6 and TNF-α through ELISA. Results Compared to the APP/PS1 mice without any treatment, SZRD, especially the L-SZRD, significantly ameliorated cognitive impairment of the APP/PS1 mice with decreases in the loss of neurons and Aβ plaque deposition as well as improvement of synaptic plasticity in the hippocampus (P < 0.05 or 0.01). Also, SZRD, in particular, the L-SZRD markedly inhibited the serum and hippocampal concentrations of IL-6, IL-1β and TNF-α, while reducing the expression of p-JAK2-Tyr1007 and p-STAT3-Tyr705 in the hippocampus of the APP/PS1 mice (P < 0.05 or 0.01). Conclusions The SZRD, especially the L-SZRD, may improve the cognitive impairment and ameliorate the neural degeneration in APP/PS1 transgenic mice through inhibiting Aβ accumulation and neuroinflammation via the JAK2/STAT3 pathway.

scholarly journals Activated STAT3 signaling pathway by ligature-induced periodontitis could contribute to neuroinflammation and cognitive impairment in rats

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Yi Hu ◽  
Xu Zhang ◽  
Jing Zhang ◽  
Xinyi Xia ◽  
Huxiao Li ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Cognitive Function ◽  
Locomotor Activity ◽  
Bone Resorption ◽  
Signaling Pathway ◽  
Alveolar Bone ◽  
Periodontal Tissue ◽  
Rt Pcr ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

Abstract Background Increasing evidence suggests a causal link between periodontitis and cognitive disorders. Systemic inflammation initiated by periodontitis may mediate the development of cognitive impairment. Our study aims to investigate the effect of ligature-induced periodontitis on cognitive function and the role of signal transducers and activators of transcription 3 (STAT3) in this process. Materials and methods Ligature-induced periodontitis was established, and the rats were treated intraperitoneally with/without the pSTAT3 inhibitor cryptotanshinone (CTS). Alveolar bone resorption and periodontal inflammation were detected by micro-computed tomography analysis and histopathological evaluation. Locomotor activity and cognitive function were evaluated by the open field test and the Morris water maze test, respectively. The activation of microglia and astrocytes in the hippocampus and cortex was assessed by immunohistochemistry (IHC). The expression of interleukins (IL-1β, IL-6, IL-8, IL-21) in both the periphery and cortex was evaluated by RT-PCR and ELISA. The expression of TLR/NF-κB and ROS cascades was evaluated by RT-PCR. The expression of pSTAT3 and the activation of the STAT3 signaling pathway (JAK2, STAT3, and pSTAT3) in the periodontal tissue and cortex were assessed by IHC and Western blot. The expression of amyloid precursor protein (APP) and its key secretases was evaluated by RT-PCR. The level of amyloid β-protein (Aβ) and the ratio of Aβ1-40/1-42 were measured via ELISA in the plasma and cortex while IHC was used to detect the level of Aβ1-42 in the brain. Results In periodontal ligature rats, significant alveolar bone resorption and local inflammatory cell infiltration were present. Apparent increases in inflammatory cytokines (IL-1β, IL-6, IL-8, and IL-21) were detected in peripherial blood and brain. Additionally, spatial learning and memory ability was impaired, while locomotor activity was not affected. Activated microglia and astrocytes were found in the cortex and hippocampus, presenting as enlarged cell bodies and irregular protrusions. Levels of TLR/NF-kB, PPAR and ROS were altered. The STAT3 signaling pathway was activated in both the periodontal tissue and cortex, and the processing of APP by β- and γ-secretases was promoted. The changes mentioned above could be relieved by the pSTAT3 inhibitor CTS. Conclusions Ligature-induced periodontitis in rats resulted in systemic inflammation and further abnormal APP processing, leading to cognitive impairments. In this progress, the activation of the STAT3 signaling pathway may play an important role by increasing inflammatory load and promoting neuroinflammation.

scholarly journals Dl-3-n-Butylphthalide Alleviates Hippocampal Neuron Damage in Chronic Cerebral Hypoperfusion via Regulation of the CNTF/CNTFRα/JAK2/STAT3 Signaling Pathways

2021 ◽  
Vol 12 ◽  
Author(s):  
Wenxian Li ◽  
Di Wei ◽  
Zheng Zhu ◽  
Xiaomei Xie ◽  
Shuqin Zhan ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Signaling Pathways ◽  
Neuronal Death ◽  
Neuronal Apoptosis ◽  
Vascular Cognitive Impairment ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Stat3 Pathway ◽  
Stat3 Signaling

Chronic cerebral hypoperfusion (CCH) contributes to cognitive impairments, and hippocampal neuronal death is one of the key factors involved in this process. Dl-3-n-butylphthalide (D3NB) is a synthetic compound originally isolated from the seeds of Apium graveolens, which exhibits neuroprotective effects against some neurological diseases. However, the protective mechanisms of D3NB in a CCH model mimicking vascular cognitive impairment remains to be explored. We induced CCH in rats by a bilateral common carotid artery occlusion (BCCAO) operation. Animals were randomly divided into a sham-operated group, CCH 4-week group, CCH 8-week group, and the corresponding D3NB-treatment groups. Cultured primary hippocampal neurons were exposed to oxygen-glucose deprivation/reperfusion (OGD/R) to mimic CCH in vitro. We aimed to explore the effects of D3NB treatment on hippocampal neuronal death after CCH as well as its underlying molecular mechanism. We observed memory impairment and increased hippocampal neuronal apoptosis in the CCH groups, combined with inhibition of CNTF/CNTFRα/JAK2/STAT3 signaling, as compared with that of sham control rats. D3NB significantly attenuated cognitive impairment in CCH rats and decreased hippocampal neuronal apoptosis after BCCAO in vivo or OGD/R in vitro. More importantly, D3NB reversed the inhibition of CNTF/CNTFRα expression and activated the JAK2/STAT3 pathway. Additionally, JAK2/STAT3 pathway inhibitor AG490 counteracted the protective effects of D3NB in vitro. Our results suggest that D3NB could improve cognitive function after CCH and that this neuroprotective effect may be associated with reduced hippocampal neuronal apoptosis via modulation of CNTF/CNTFRα/JAK2/STAT3 signaling pathways. D3NB may be a promising therapeutic strategy for vascular cognitive impairment induced by CCH.

scholarly journals JAK2/STAT3 Signaling Pathway Plays a Key Role in Nicotine Mediated Neuroinflammation Suppression in an Ischemic Rat Model

2021 ◽  
Author(s):  
Qi Wang ◽  
Tingting Han ◽  
Ruihe Lai ◽  
Dalong Zhang ◽  
Yao Diao ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Signaling Pathway ◽  
Rat Model ◽  
Inflammatory Factors ◽  
Spatial Learning And Memory ◽  
Sham Operation ◽  
Micropet Imaging ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Significant Difference

Abstract BackgroundTo explore the mechanism of nicotine mediated improvement of cognitive impairment in an established ischemic rat model. MethodsEndothelin-1 (ET-1) was injected into the left thalamic region in adult male Sprague-Dawley (SD) rats to establish ischemia model. 6 groups of rats (6 rats in each group) were then treated with nicotine, nicotine+DHβE, DHβE, AG490, nicotine +AG490 and saline respectively via intraperitoneal injection for 9 days. Another sham operation group was treated with saline as above. Morris Water Maze (MWM) test was performed for 6 consecutive days starting on the 4th day after operation to detect the cognitive function of rats in each group. 2-[18F]-A-85380 microPET imaging was performed on day 10 to evaluate the changes of α4β2 nAChRs in different brain regions of rats. Real-time PCR and Western blot were used to detect the amount of α4β2 nAChRs, JAK2, STAT3 and inflammatory factors in thalamus of rats in each group. ResultsThe results of MWM test showed the spatial learning and memory abilities of rats in the nicotine and sham operation groups were significantly better than the saline treating group in this ischemic rat model (p<0.05). There was no significant difference in other groups (p>0.05). MicroPET imaging showed more uptake of 2-[18F]-A-85380 in the nicotine, nicotine+AG490 and sham operation groups than in saline treating group, while there was no significant difference found in other groups (p>0.05). The expression of α4- and β2-nAChR in nicotine, nicotine+AG490 and sham operation groups was significantly higher than the saline treating group (p<0.05). In the nicotine group, the expression of p-JAK2 and p-STAT3 in left thalamus of rats was significantly higher than the saline treating group (p<0.05), and the expression of IL-1β and IL-6 protein was found to be lower than the saline treating group (p<0.05). While the expression of p-JAK2, p-STAT3 and inflammatory factors was not significantly different in all the other groups (p>0.05). ConclusionThe study suggests nicotine inhibits the expression of inflammatory factors by activating α4β2 nAChRs through the activation of JAK2-STAT3 signaling pathway to improve cognitive impairment in ischemic rats.

scholarly journals Activated STAT3 Signaling Pathway by Ligature-induced Periodontitis Could Contribute to Neuroinflammation and Cognitive Impairment in Rats

2020 ◽  
Author(s):  
Yi Hu ◽  
Xu Zhang ◽  
Jing Zhang ◽  
Xinyi Xia ◽  
Huxiao Li ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Cognitive Function ◽  
Locomotor Activity ◽  
Bone Resorption ◽  
Oral Cavity ◽  
Signaling Pathway ◽  
Alveolar Bone ◽  
Rt Pcr ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

Abstract Background: Increasing evidence suggests a causal link between periodontitis and cognitive disorders. Systemic inflammation initiated by periodontitis may mediate the development of cognitive impairment. Our study aims to investigate the effect of ligature-induced periodontitis on cognitive function and the role of Signal transducers and activators of transcription 3 (STAT3) in this process.Materials and Methods: Ligature-induced periodontitis was established, and the rats were treated intraperitoneally with/without the pSTAT3 inhibitor cryptotanshinone (CTS). Alveolar bone resorption and periodontal inflammation were detected by micro-computed tomography (micro-CT) analysis and histopathological evaluation. Locomotor activity and cognitive function were evaluated by the Open field test (OFT) and the Morris water maze test (MWM), respectively. The activation of microglia and astrocytes in hippocampus and cortex was assessed by immunohistochemistry (IHC). The expression of interleukins (IL-1β, IL-6, IL-8, IL-21) in both periphery and cortex was evaluated by RT-PCR and ELISA. The expression of pSTAT3 and the activation of the STAT3 signaling pathway (JAK2, STAT3, and pSTAT3) in both oral cavity and cortex was assessed by IHC and Western blotting. The expression of amyloid precursor protein (APP) and its key secretase enzymes were evaluated by RT-PCR. The level of amyloid β-protein (Aβ) and the ratio of Aβ1-40/1-42 were measured via ELISA in plasma and cortex while IHC was used to detect the level of Aβ1-42 in brain.Results: In periodontal ligature rats, significant alveolar bone resorption and local inflammatory cell infiltration were present. Apparent increases in inflammatory cytokines (IL-1β, IL-6, IL-8 and IL-21) were detected. in both periphery and brain. Additionally, spatial learning and memory ability was impaired, while locomotor activity was not affected. Activated microglia and astrocytes were found in the cortex and hippocampus, presenting as enlarged cell bodies and irregular protrusions. The STAT3 signaling pathway was activated in both oral cavity and cortex and the processing of APP by β- and γ-secretases was promoted. Change mentioned above could be relieved by the pSTAT3 inhibitor CTS. Conclusions: Ligature-induced periodontitis in rats resulted in systemic inflammation and further abnormal APP processing, leading to cognitive impairments. In this progress, the activation of the STAT3 signaling pathway may play an important role by increasing inflammatory load and promoting neuroinflammation.

Melatonin Ameliorates Axonal Hypomyelination of Periventricular White Matter by Transforming A1 to A2 Astrocyte via JAK2/STAT3 Pathway in Neonatal Rats Induced by Lipopolysaccharide Injection

2021 ◽  
Author(s):  
Shuqi Jiang ◽  
Huifang Wang ◽  
Qiuping Zhou ◽  
Qian Li ◽  
Nan Liu ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
White Matter ◽  
Neurological Dysfunction ◽  
Periventricular White Matter ◽  
Neonatal Rats ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Tnf Α ◽  
Phenotype Transformation

Abstract Background: Astrocyte A1/A2 phenotypes may play differential role in the pathogenesis of periventricular white matter (PWM) damage in septic postnatal rats. In this study, we sought to determine whether melatonin(MEL) would improve the axonal hypomyelination and neurological dysfunction, and, if so, to ascertain whether this may be related to transformation of astrocyte A1 to A2 phenotype.Methods: One-day-old Sprague–Dawley rats were divided into control, LPS, and LPS+MEL groups. Immunofluorescence was performed to detect IBA1, GFAP, MAG, C3 and S100A10 in the PWM of neonatal rats. C1q, IL-1α and TNF-α expression were assessed by immunofluorescence and ELISA. Electron microscopy was conducted to observe alterations of axonal myelin sheath in the PWM, and the number of PLP and MBP positive oligdendrocytes was caculated using in situ hybridization. The effects of MEL on locomotor ability, spatial learning and memory were evaluated by behavioral testing. In vitro, A1 astrocyte was induced by IL-1α, C1q and TNF-α, the effect of MEL on C3 and S100A10 expression was determined by Western blot and immunofluorescence. JAK2/STAT3 signaling pathway was investigated to determine whether it was involved in modulation of A1/A2 phenotype transformation.Results: At 1 and 3 days after LPS injection, IBA1+ microglia in the PWM were significantly increased in cell numbers which generated excess amounts of IL-1α, TNF-α, and C1q. The number of A1 astrocytes was significantly increased at 7-28d after LPS injection. In rats given MEL treatment, the number of A1 astrocytes was significantly decreaed, but that of A2 astrocytes, PLP+, MBP+ and MAG+ cells was increased. By electron microscopy, ultrastructural features of axonal hypomyelination were attenuated by MEL. Furthermore, MEL improved neurological dysfunction as evaluated by different neurological tests. In vitro, MEL decreased the C3 significantly, and upregulated expression of S100A10 in primary astrocytes subjected to IL-1α, TNF-α and C1q treatment. Additionally, JAK2/STAT3 signaling pathway was found to be involved in modulation of A1/A2 phenotype transformation. Conclusions: MEL effectively alleviates PWMD of septic neonatal rats, and that it is most likely through modulating astrocyte phenotypic transformation from A1 to A2 via the MT1/JAK2/STAT3 pathway.

Acute Monocytic Leukemia Associated Antigen MLAA-34 up-Regulates JAK2/STAT3 Expression and JAK2/STAT3 Enhances MLAA-34 Activation in a Positive Feedback Loop

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1393-1393
Author(s):  
Bo Lei ◽  
Ju Bai ◽  
Wanggang Zhang ◽  
Aili He ◽  
Yinxia Chen ◽  
...  
Keyword(s):  
Western Blot ◽  
Signaling Pathway ◽  
Expression Vectors ◽  
Acute Monocytic Leukemia ◽  
U937 Cells ◽  
Rt Pcr ◽  
Monocytic Leukemia ◽  
Stat3 Pathway ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

Abstract Backgroud: The MLAA-34 gene (GenBank no. AY288977.2) was first discovered in acute monocytic leukemia (M5) in an effort to identify monocytic leukemia-associated antigens by serologic analysis of a recombinant cDNA expression library (SEREX). Previous study showed that high MLAA-34 levels were independently associated with a poorer relapse-free survival and overall survival in AML patients. The MLAA-34 is located on 13q14.2 and has been confirmed to be a novel splice variant of CAB39L (calcium binding protein 39-like). Both mRNA and protein levels of MLAA-34 were found to be higher in U937 cells and M5 patients. The study confirmed that MLAA-34 plays a role in the antiapoptosis of U937 cells, and has the function of oncogenes. Objective: This study is to explore the relationship of MLAA-34 and JAK2/STAT3 signaling pathway so as to further clarify antiapoptotic mechanisms of MLAA-34. Method: Potential binding sites for STAT3 was identified by computer-assisted analysis of the core promoter of MLAA-34 gene. We analyzed the role of STAT3 in the regulation of MLAA-34 gene expression in U937 cells by site-specific mutation, chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA). The expression of MLAA-34 was detected by RT-PCR and western blot after over-expressing and interfering STAT3. Through the different concentrations of AG490 (JAK2 inhibitors) and different concentrations of IL- 6 (JAK2 activator) study JAK2/STAT3 signaling pathway upregulated MLAA-34 expression. The gene chip and co-IP were applied to study the MLAA-34-induced JAK2/STAT3 activation. Peripheral blood mononuclear cells and bone marrow (BM) cells of M5 patients were obtained. In M5 patients, mRNA and protein expression of JAK-2, STAT3, p-STAT3 and MLAA-34 were determined by quantitative RT-PCR and western blot respectively to verify the forward feedback regulation pathway. Result: The reporter assay showed that the activity of reporter gene was downregulated after the mutation of STAT3 binding sites. ChIP assay and EMSA showed that STAT3 can directly bind to MLAA-34 gene promoter. The expression vectors of MLAA-34 as well as siRNA eukaryotic expression vectors respectively targeting STAT3 were successfully constructed. RT-PCR and western blot results showed that STAT3 can increase the level of MLAA-34. Research of administration of different concentrations of AG490 and different concentrations of IL-6 showed that JAK2/STAT3 signaling pathway could upregulate MLAA-34 expression. AML-M5 NOD / SCID mice leukemia model was successfully constructed,.Konckdown of MLAA-34 gene can promote apoptosis of leukemia cells, inhibit tumor growth and prolong survival time. Total RNA from shRNA-MLAA-34/U937 and Vec/U937 cells were analyzed by Human Genome U133 chip. Heat-map showed reduced expression of JAK2/STAT3 pathway genes. The result was verified by qPCR and western blot. CO-IP showed that MLAA-34 could form a complex with endogenous JAK2 under the enhanced role of IL-6. Thereby activating JAK2 may directly or indirectly dependent on the presence of MLAA-34. Furthermore, we detected JAK-2, STAT3, P-STAT3 and MLAA-34 gene and protein level in M5 patients, the results showed that they have a positive correlation. Conclusion: JAK2/STAT3 pathway up-regulates MLAA-34 transcription, and MLAA-34 enhances JAK2/STAT3 pathway activation. The forward feedback regulation may have profound therapeutic implications for M5 and could help invent novel approaches in treatment for acute monocytic leukemia. Disclosures No relevant conflicts of interest to declare.

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